4-methyl-17-alpha-hydroxy-progesterone and esters thereof



United States Patent 3,102,896 4-METHYL-17-ALPHA-HYDROXY-PROGESTERONEAND ESTERS THEREOF John C. Bahcock, Portage Township, Kalamazoo County,and Raymond L. Pederson, Kalamazoo, Mich, assignors to The UpjohnCompany, Kalamazoo, Mich,

a corporation of Michigan No Drawing. Filed June 2, 1958, Ser. No.738,929 3 Claims. (Cl. zen-397.4

The present invention relates to new steroids and, is more particularlyconcerned with certain 4-a1kyl-4-pregnene-3,20-diones, to novelintermediates in the production thereof and to processes for theproduction of the novel compounds and novel intermediates.

The novel 4-alkyl-4-pregnene-3,ZO-diones of this invention, particularlythe 4 methy=l compounds thereof, are important physiologically activecompounds. They possess central nervous system regulatory,antihormona-l, particularly anticorticoid and antiprogestational,antifungal, and hypotensive activities. The novel compounds of thisinvention can be prepared and administered in a Wide variety of oral orparenteral dosage forms singly, or in admixture with other coastingcompounds. They can be associated with a pharmaceutical carrier whichcan be a solid material or a liquid in which the compound is dissolved,dispersed or suspended. The solid compositions can take the form oftablets, powders, capsules, pills or the like, preferably in unit dosageforms for simple administration or precise dosages. The liquidcompositions can take the form of solutions, emulsions, suspensions,syrups or elixirs. The novel compounds can also be administeredtopically in the formof ointments, creams, lotions and the like, with orwithout coacting anti- 'biotics, germicides or other materials formingadvantageous compositions therewith.

The novel compounds of this invention are in addition useful asintermediates for the production of the corresponding l-dehydrosteroids. Microbiological dehydrogenation of the4-allcyl-4-pregnene-3,20-diones, represented by Formula I, withSeptomyxa afiinis, A.T.C.C. 6737, under the fermentation conditionsdescribed in US. 2,602,769, is productive of the correspondingl-dehydrocompounds, e. g., 1-dehydro-4-alkyl-progesterone, l-dehydro17a-hydroXy-4-alkyl-progesterone, 1-dehydro-4-alkyl-desoxycorticosterone, and 17u,2l-dihdroxy-4-alkyl-1,4-pregnadiene-3,ZO-dione. Of these, the 4-methyl compounds arepreferred. During the fermentation with Septomym afiinis, ester groupswhen present in the starting material will, generally, be hydrolyzed.Acylation of the resulting free hydroxyl groups either at the 17- or211-positions or both can be accomplished using the acylating agents andprocedures hereinafter described for acyl- 'ating the correspondingl-ncndehydrogenated compounds of this invention. These compounds, thel-dehydro analogues of the compounds of this invention, are alsophysiologically active agents, with improved therapeutic ratios. Theypossess the same general spectrum of activity as the compounds of thisinvention such as central nervous system regulatory, antihormonal,antifungal, and hypotensive activity.

CHeR' R wherein R is a lower-alkyl radical containing from one to fourcarbon atoms, inclusive, and wherein R is hydrogen, hydroxyl, or AcO,wherein Ac is the acyl radical of an organic carboxylic acid, preferablyan aliphatic hydrocarbon carboxylic acid, containing from one to twelvecarbon atoms, inclusive.

It is an object of the present invention to provide certainphysiologically active 4-alkyl-4-pregnene-3,20-diones. It is anotherobject of this invention to provide the novel intermediates, the3-enamines of the novel 4-alkyl-4-pregnene-3,20-diones. It is anotherobject of the present invention to provide a process for the productionof the novel 4-alkyl-4-pregnene-3,ZO-diones. Other objects of thisinvention will be apparent to those skilled in the art to which thisinvention pertains.

The process of the present invention comprises: treating a4-pregnene-3,20-dione with a secondary cyclic amine to produce thecorresponding B-enamine. The 3-enamine thus produced is then allowed toreact with an alkylating agent to produce the S-enamine of a 4-alkyl-4-pregnene-3,20-dione, which compound on hydrolysis yields a4-alkyl-4-pregnener3,ZO-dione. Acylation of the hydroxyl groups in those4-alkyl-4-pregnene-3,20-diones in which hydroxyl groups are present isproductive of the corresponding 17- or ZI-acylates, or the17,2l-diacylates.

The compounds of the present invention can be prepared fromprogesterone, 17a-hydroxyprogesterone, desoxycoricosterone, and17a,2l-dihydroxy-4-pregnene-3,20-dione .(Reichsteins Compound S), byfollowing the above general procedure, or by certain alternates, as willbe described more fully below.

According to the process of the present invention, the ketone group atthe 3-position of a 4-pregnene-3,20- dione is converted to the S-enaminederivative by reaction with a secondary cyclic amine. Amines which canbe used are pyrrolidine, morpholine, pipenidine, homomorpholine, C-alkylsubstituted pyrrolidines, e.g., 2,4 dimethylpyrrolidine,3-isopropylpyrrolidine, 3,3-dimethylpyrrclidine and the like; of theseamines, pyrrolidine is preferred. The selected amine is usually used ina molar excess, calculated on the starting steroid, to achieve theoptimum yield of enamine product. Although large molar equivalentexcesses of the amine can be employed in the reaction, the preferredproportion of amine to starting steriod is usually from about 1.1 toabout seven moles of amine per mole of steroid with excellent resultsobtainable in the range of about 1.1 to two moles of amine per mole ofsteroid.

Moisture in the reaction is somewhat detrimental to the procurement ofhigh yields of product, and preferred aroasee reaction conditionstherefore include removal of the water formed during the enamineformation by known methods. The reaction is preferably conducted aboveroom temperature, i.e., above about 25 degrees centigrade, e.g., betweenabout 25 and 150 degrees centigrade. Reaction times may vary betweenabout a few minutes to several days, depending in part upon the reactionsolvent or solvents, ratio of reactants, selected amine, rate of waterremoval and temperature. Reaction solvents employed are benzene,toluene, xylene, chlorobenzene, pentan'e, hexane, chloroform, methylenechloride, carbon tetnachloride, methanol, ethanol, tertiary butylalcohol, tetrahydrofuran, dioxane, and the like.

The 3-enamine of the 4-pregnene-3,20-dione thus produced is thenalkylated in a dry inert organic solvent such as ethanol, methanol,isopropanol, butanol, tetrahydroturan, ethyl acetate, and the like, withan excess of alkyl- 'atin'g agent such as an alkyl halide, to producethe 4- alkyl-S-enamine of the 4-pregnene-3,20-dione. Alkyl A halidesthus employed are those wherein the alkyl group has from one to fourcarbon atoms, inclusive, and the halogen is chlorine, bromine or iodinewith bromine and iodine generally preferred. Representative alkylhalides include methyl, ethyl, propyl, isopropyl, butyl, isobutylbromide and iodide. The corresponding. alkyl chlorides are alsooperative but usually give somewhat inferior yields.

A preferred method is to treat the 3-enamine of the pregnene-3,20-dionewith an excess of alkyl iodide in dry methanol and reflux for period ofabout eight to 24 hours, until the reaction is complete. At the end ofthe reflux period, the excess alkyl iodide is removed by distillationand the 4-alkyl-3-enamine is isolated, if desired, or is hydrolyzedwithout isolation. For best yields it is sometimes advantageous toconduct the enamine formation and alkylation steps in an atmosphere ofnitrogen. lllustrative of the enamines that can be thus produced are3-pyr11olidylenamine of 4-methylprogesterone, 3-pyrrolidyl enamine of4-methyldesoxycorticosterone, 3-pyrrolidyl enamine of4-methyl-'17a-hydroxyprogesterone, 3- pyrrolidyl enamine of 4-methyl-l7u,2l-dihydroxyl-pregn'ene-3,20-dione, and the like.

The 3-enamine of the 4-alkyl-4-pregnen-3,ZO-dione thus produced can thenbe hydrolyzed with water, aqueous acid or base, or alk-anol watermixtures. This treatment removes the 3-enamine group and results inregeneration of the A -3-keto group in the steroid nucleus, withproduction of the corresponding 4-alkyl-4pregnene3,20- dione. Apreferred method for the hydrolysis of the 3-enamine group is in anaqueous-methanol sodium hydroxide solution, or in a water-methanolmixture, the water-methanol mixture being of particular advantage whenester groups that might be hydrolyzed with the base are present in themolecule; The hydrolysis mixture is heated under reflux for a period ofabout twenty minutes to about three hours, and is then either dilutedwith Water or first concentrated by distillation to remove most of themethanol present and then diluted with water. When on dilution acrystalline product is obtained, it is isolated by filtration. When theproduct is not crystalline, the mixture is extracted with ether,methylene chloride, benzene, toluene, hexan'e or the like. The extractis then washed, dried, andv the solvent removed by distillation, givingthe 4-alkyl-4-pregnene-3,20 dione corresponding to the startingmaterial, such as for example, 4-alkyl progesterone,4-alkyl-17u-hydroxyprogesterone, 4-alkyldesoxycorticosterone, and 4alkyl 170:,21 dihydroxy-4- pregnene-3,20-dione. The compounds thusproduced can be purified by chromatography or recrystallization, orboth.

The compounds of this invention, represented by Formula I, can beutilized either as the free alcohols or as the esters. Acylation of thehydroxyl groups either at the 17- or 2l-positions, or both, when suchhydroxylv groups are present at those positions, is accomplished byallowing the hydroxy compounds to react with the anhydride of an organiccarboxylic acid, preferably a hydrocarbon carboxylic acid containingfrom one to twelve carbon atoms, inclusive, for example, a saturatedstraightchain aliphatic acid, e.g., acetic, propion-ic, butyric,valeric, hexanoic, lauric, a saturated branched-chain aliphatic acid,e.g., trimethylacetic, isobutyric, isovaleric, a cycloaliphaticsaturated acid, e.g., cyclohexanecanboxylic acid, an alkaryl acid, e.g., phenylacetic, Z-phenylpropionic, 0-, m-, and p-tol-uic, a saturateddibasic acid (which can be converted into water-soluble, e.g., sodium,salts), e.g. succinic, adipic,. a monobasic unsaturated acid, e.-g.,acrylic, crotonic, undecylcnic, propiolic, cinnamic, a dibasicunsaturated acid (which can be converted into water-soluble, e. g.,sodium, salts), e. g., maleic and citraconic. I

Illustrative of the esters thus produced are the 4-alkyl and moreparticularly the 4-methyl acylates such as the l7-monoacylates, e.g.,4-methyl-l7a-hydroxyprogesterone 17-acetate, 4 methyl 17 0chydroxyprogesterone 17-propionate, 4-methyl-17a-hydroxyprogesterone17-phenylacetate; the ZI-acylates such as, for example,4-methyldesoxycorticosterone 2l-acetate, 4-methyldesoxycorticosterone21-hemisuccinate, 4-methyldesoxycorticosterone ZI-isovalerate,4-methyldesoxycorticosterone 2l-maleate; the l7,2ldiacylates such as,for example, 4-methyl-17a, 2l-dihydroxy-4-pregnene-3,ZO-dione17,2l-diacetate, methyl-l7a,21-dihydroxy-4-pregnene-3,ZO-dione17,21-dipropionate, 4 methyl-17oc,21-dihydroxy-4-pregnene-3,20- dione17,2l-propiolate, and the like.

In esterifying the 4-alkyl-17a,2l-dihydroxy-4-pregnene- 3,20-dionecompounds of this invention, vigorous esterification conditions,"such asfor example, heating with the appropriate acid 'anhydride at about todegrees centigrade is productive of the corresponding diacylates. Mildesterification conditions such as, for example, allowing the selected 4-all yl-l7a,2l-dihydroxy-4-pregnene-3,20 dione compound to react withtheappropriate acid anhydride in solution in pyridine at roomtemperature is productive 'of the 2l-monoacylate.4-alkyl-17a,21-dihydroxy- 4-pregnene-3,20-dione Zl-acylates and moreparticularly 4-- rnethyl-17ot,2l-dihydroxy-4-pregnene-3,ZG-dione2l-acylates that can bethus produced include, for example, 4-methyl-l7u,2l-di-hydroxy 4 pregnene-3,20-dione Zl-acetate, 4-methyll7c,2l-dihydroxy-4-pregnene-3,20=dione 21- cortonate,4-methyl-l7a,21-dihydroxy-4-pregnene-3,20-dione ZI-butyrate, and thelike.

Alternatively, the 4-alkylated acyloxy compounds of this invention,i.e., the 17- or ZI-monoacylates or the 17,21- diacylates, representedby Formula I, may be prepared from the appropriate non-alkylated acyloxystarting material according to the steps hereinbefore described, i.e.,formation of the B-enamine, followed by alkylation at the 4aposition,and finaly removal of the enamine blocking group.

The following examples are illustrative of the process and products ofthe present invention, but are not to be construed as limiting.

EXAMPLE 1 4-Methyl-4Pregnene 3,20-DiOne (i-Methylprogsterone) A solutioncontaining thirteen grams of progesterone in sixty milliliters of drymethanol was prepared by Warming until the progesterone had dissolve andto this solution was added ten milliliters of pyrrolidine with stirring.After one minute rapid crystallization occurred. The reaction mixturewas allowed to stand for ten minutes and was then cooled and thecrystalline 3-pyrrolidyl enamine of progesterone was filtered, washedwith twenty milliliters of methanol and with twenty milliliters ofether.

A mixture containing the above 3-pyrrolidyl enamine of progesterone, 300milliliters of absolute methanol, and thirty milliliters of methyliodide was warmed to reflux.

in about one to five minutes.

After about one hour solution was complete and reflux continued forseventeen hours. The excess methyl iodide was removed at the end of thereflux period by removing 180 milliliters of distillate by distillation.An aqueous solution of twenty milliliters of ten percent sodiumhydroxide was added and the resulting mixture was heated at reflux forone and one-half hours. The solution was concentrated under reducedpressure distillation to about fifty milliliters and cooled. Theconcentrate was extracted with ether and the extract was washed withdilute acid, dilutealkali and water until neutral. The solution wasdried over sodium sulfate and then concentrated to a syrup weighing 8.5grams. The syrup was dissolved in fifty milliliters of methylenechloride and 100 milliliters of Skellysolve B hexanes and was adsorbedon 450 grams of synthetic magnesium silicate in a chromatographiccolumn. The column was eluted with 200 milliliter fractions of acetonein Skellysolve B hexanes as follows:

Fraction No.: Solvent 1-10 ..Acetone-Skellysolve B hexanes (3:97) 1l-41Acetone-Skellyso1ve B hexanes (4:96)

Fractions 23 through 31 were evaporated to dryness and the crystallineresidues combined (1.9 grams) and recrystallized fromacetone-cyclohexane to give 1.13 grams of 4-methyl-4-pregnene-3,20 dionehaving a melting point of 160 to 166 degrees centigrade, a rotation of[a1 plus 173 degrees (dioxane) and a ultraviolet absorption of was,250.5 111,. (a 15,450) Arialysis.Calculated for C H O C, 80.44; H, 9.82.Found: C, 80.06; H, 9.96. 7

EXAMPLE 2 4-M ethy [-1 7 a-H ydroxy-4-Pregnene-3,Z0-Dione 1 7-A cetate Asolution containing fifty grams of 17u-hydroxy-4- pregnene-3,20'-dionel7-acetate in 150 milliliters of methylene chloride and 500 millilitersof methanol was concentrated by boiling until most of the methylenechloride was removed (to about a volume of 500 to 550 milliliters). Thesolution was then cooled about five degrees, placed under nitrogen, and25 milliliters of pyrrolidine added thereto. Crystallization took placeat this temperature The mixture was then cooled and the product filteredto give 55 .75 grams of the 3-pyrrolidyl enamine of17ot-acetoxy-4-pregnene-3,20-dione of melting point 205 to 225 degreeswith decomposition. i

To a suspension of fifteen grams of the above Z-p-yrrolidyl enamine of17u-hydroxy-4-pregnene-3,20-dione 17- acetate in 75 milliliters ofmethanol, While being stirred and under nitrogen, was added thirtymilliliters of methyl iodide and the mixture was heated to reflux.Twenty milliliters of methylene chloride was added and the resultingsolution was allowed to reflux for seventeen hours after which it wasconcentrated to about fifty milliliters and diluted with fiftymilliliters of water. The resulting solution was allowed to reflux forforty minutes and was then cooled and diluted with fifty milliliters ofwater to cause precipitation of 2.62 grams of crude solid which wasisolated by filtration. The filtrate was extracted successively withbenzene and with ether and the extracts were combined, washed withdilute hydrochloric acid, dilute sodium bicarbonate, and water, andchromatographed over syn thetic magnesium silicate. The product,4-methyl-17uhydroxy-4-preguene-3,20-dione l7-acetate which Was elutedwith four percent acetone in Skellysolve B hexanes weighed 1.1 grams andafter two recrystallizations from methylene chloride-methanol melted at175 to 180 degrees centigrade and had a rotation of [ab plus 86 deees.Analysis.Calculated fOl' C24H3404I C, H, 8.87. Found: C, 74.28; H, 8.85.

Following the procedure of the above example and substitutingl7a-hydroxyprogesterone as starting material therein is productive ofthe intermediate compound, the 3-pyrrolidyl enamine of4-methyl-l7a-hydroxyprogesterone, which on hydrolysis gives 4-methy1-l7a-hYdIOXYPIO- gesterone.

Following the procedure of Example 2 above, and substituting otherl7a-hydroxy-4-pregnene-3,20-dione 17- acylates for17a-hydroxy-4-pregnene-3,20-dione 17-acetate as starting materialtherein is productive of other 4 methyl 17a hydroxy 4 pregnene 3,20dione 17-acylates, preferably those wherein the acyl radical is that ofan organic carboxylic acid, preferably a hydrocarbon carboxylic acidcontaining from one to twelve carbon atoms, inclusive. Illustrative ofthe 17-acylate compounds that can be thus produced are4-methyl-l7u-hydroXy-4-pregnene-3,20-dione 17-propionate,4-methyll7a-hydroxy-4-pregnene-3,20-dione l7-butynate, 4-methyl-17a-hydroxy-4-pregnene-3,20-dione 17-phenylacetate, 4-methyl-17a-hydroxy-4-pregnene-3,20-dione 17-acrylate, 4- methyl 17ahydroxy 4 pregncn 3,20 dione 17 trimethylacetate, and the like.

In like manner substituting a 2l-hydroxy-4-pregnene- 3,20-di0neZl-acylate or 17a,21-dihydroxy-4-pregnene- 3,20-dione 17,21-diacylate asstarting material in Example 2 above is productive of the corresponding4-methyl- 21-hydroxy-4-pregnene-3,ZO dione 21-acetate or 4-methyl-17,2l-dihydroxy-4-preguene-3,ZO-dione 17,2l-diacylate. The preferredacyloxy and diacyloxy compounds are those wherein the acyl radical isthat of an organic carboxylic acid, preferably a hydrocarbon carboxylicacid containing from one to twelve carbon atoms, inclusive.

EXAMPLE 3 4 Methyl 21 Hydroxy 4 Pregnene 3,20 Dione(4-Methyldesoxycorticosterone) In essentially the same manner asdescribed in Examples 1 and 2, desoxycorticosterone was converted to thecorresponding 3-pyrrolidyl enamine with pyrrolidine and the 3-enaminecompound was methylated with methyl iodide to give the 3-pyrrolidylenamine of 4-methyldesoxycor-ticosterone which on hydrolysis gave4-methyl-2l-hydroxy-4-pregnene-3,20 -dione of melting point 140.5 to144.5 degrees centigrade after two recrystallizations from aqueousmethanol.

EXAMPLE 4 4 Methyl :,21 Dihydroxy 4 Pregnene 3,20-

Dione In essentially the same manner as described in Examples 1 and 2,170:,21-dihydroxy-4-pregnene-3,20-dione was converted to thecorresponding 3-pyrrolidyl enamine with pyrrolidine and the 3-enaminecompound was methylated with methyl iodide, to give the 3-pyrrolidylenamine of 4-methyl-1 7u,21-dihydroxy-4-pregnene-3,ZO-dione, which onhydrolysis gave 4-methyl-17m,21-dihydroxy-4-pregnene-3,20-dione.

Following the procedures described in Examples 1, 2, 3 and 4 alkylationwith other alkyl halides, particularly with a loweralkyl halide whereinthe alkyl radical contains from one to four carbon atoms, inclusive,such as for example methyl, ethyl, propyl, isopropyl, butyl and isobutylbromide or iodide, is productive of other 4-a1ky1-4-pregnene-3,20-dionessuch as for example,

4-ethyl-4-pregnene-3,20-dione, 4-isopropyl-4-pregnene-3,20-dione,4-butyl-21-hydroxy4-pregnene-3,20-dione,4-isobutyl-21-hydroxy-4-pnegnene-3,20-dione,4-propyl-17ot-hydroxy-4-pregnene-3,ZO-dione,4isobutyl-17a-hydroxy-4-pregnene-3,20-dione, 4-ethyl17a,21-dihydroxy-4-pregnene-3,ZO-dione,4-butyl-17a,21-dihydroxy-4-pregnene-3,20-dione, and the like.

awasee EXAMPLE i l l 4 Methyl 170:,21 Dihydroxy 4 Pregnene 3,20- Dione17,21-Diacetate A solution of 1.5 grams of 4-methyl-17a,21-dihydroxyfromacetone to give 4-methy1-l7qz,2l-dihydroXy-4-pregnene-3,20-dione17,2l-diacetate. I g I EXAMPLE 6 4 Methyl 17cc Hydroxy 4 Pregnene 3,20Dione 17-Acetate Following the procedure of Example 5 and substituting4-methy1-l7u-hydroxyprogesterone as starting material therein isproductive of 4-methyl-l7a-hydroXy-4-pregnene- 3,2O-di0nc 17-acetate,identical with that obtained in Example 2.

EXAMPLE 7 4 Methyl 70:,21 Dihydroxy 4 Pregnene 3,20-

Dione 21 Acetate v EXAMIPLE 8 4 Methyl 21 Hydroxy 4 Pregltene 3,20Dione.

' 21 Acetate Following the procedure of Example 7 and substituting4-methyl-21-hydroXy-4-pregnene-3,20-dione as starting material thereinis productive of 4-methyl-21-hydroxy-4- pregnene-3,20-dione 2l-acetate.

Similarly by following the acylation procedures described in Examples 5,6, 7 and 8 above, still other 17- and 21-acylates and 17,21-diacylatesare prepared by reacting a selected 4-alkyl417ot-hydroxy-4-pregnene8,20-dione, 4- alkyl-2l hydroxy-44pregnene-3,ZO-dione, or 4-alkyl-170:,21-dihydroXy-4-pregnene 4 3,20 dione with the appropriatehydrocarbon carboxylic acid anhydride. Illustrative of the esters thusproduced are 4-methyl-l7ahydroxy-4-pregnene-3,20-dione l7-propionate,4-methyl- 17a-hydroxy4-pregnene-3,2(ldione 17-fl-phenyl propionate,4-methyl-17u-hydroXy-4-pregnene 3,20 dione 17- acrylate,4-methyl-l7ot-hydroxy-4-pregnene 3,20 dione l7-thex anoate,4-n1ethyl-17a hydroxyl-pregnene-3,2 0-dione l7-rnaleate,,4-methyl-17a-hydroXy-4 pregnene-3,20- dione 17-trimethyl acetate,4-methyl-l7u-hydroxy 4-pregnene-3,2'0-d-ione l7-benzoate,4-methyl-l7a,21-dihydroxy- 4-pregnene-3,20-dione l7,2l-dibutyrate,4-inethyl-l7ot,21- dLhydroxy-4-pregnene-3,20 dione 17,21-clilaurate,4-methyl-l7a,2.1+dihydroxy-4-pregnene-3,20 dione 17,21 dicyolohexanecarboxylate, 4-methyl 17a,2l dihydroxy 4- pregnene-3,20-dione17,2l-dipropiolate, 4-methyl-l7a,2ldihydroXy-4-pregnene-3,20-dione17,21-diisobutyrate, 4-

methyl-1-7m,21-di-hydroxy-4-pregnene-3,ZO-di-one 17,21- diphenylacetate,4-methyl-l7ot,2l-dihydroxy-4-pregnene-3, 20-dione 17,21-dicrotonate,4-methyl-21-hydroXy 4-pregncne-3,20-dione 2l-valerate,4-methyl-2l-hydroXy-4-pregnene-3,20-dio'ne. 2l-isovalerate,4-methyl-21-hydroxy 4- 'pregnene-3,2(l-dione 2.l- (o-, m-, p-) toluate,4-methyl-2lhydroxy-4-pregnene-3, 20=dione ZI-hemisuccinate, 4-methy1-21-hydroXy-4-pregnene-3,ZO-dione 21-hemiadipate, 4-methyl-2l-hydroXy-4-pregnene-3,20-dione 21 crotonate,4-metl1yl-21-hydroxy-4-pregnene-3,20-dione 21-undecylenate,4-methyl-21-hydroxy-4-pregnene-3,ZO-dione 21-cinnamate,4-rnethyl-2l-hydroXy-4-pregnene-3,20 dione 21- 'citraconate, the4-ethyl, propyl, isopropyl, butyl, isobutyl analogues thereof, and thelike.

it is to be understood that the invention is not to be limited to theexact details of operation or exact com- 10 pounds shown and described,as obvious modifications and equivalents will be apparent to one skilledin the art, and the invention is therefore to be limited only by thescope of the appended claims.

We claim: a

5 1. A compound of the group consisting'of4-methyll7-alplra-hydroxyprogesterone and the esters thereof, oftheformul a:

in which R is taken from the group consisting of a hydrogen atom and anacyl radical of an aliphatic carboxylic acid containing not more thannine carbon atoms.

2. A compound of the formula:

0:0 --OAe 7 CH; where Ac is the acyl radical of a hydrocarbon carboxylicacid containing from one to twelve carbon atoms, inclusive. 3. Acompound of the formula:

. (3H8 0:0 I I --O-acetyl i CH: 7

References (Iited in the file of this patent Djerassi et 'al.: J.A.C.S.,vol 71, pages 3962-6 (1949).

lulian et a1; ibid, vol 72, pages 367- Gleason et al.: i'bid., vol. 72,pages 1751-2, Ott et al.: 'ibid., vol/74, pages 1239-41. Turner: ibid,vol. pages, 3489-92. 0 Meystre et al.: Helv. Chem. Acta, vol. 34, pp.2286- (.1951). t

1. A COMPOUND OF THE GROUP CONSISTING OF4-METHYL17-ALPHA-HYDROXYPROGESTERONE AND THE ESTERS THEREOF, OF THEFORMULA: